Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

Abstract

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4+ T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

Vasoactive intestinal peptide exerts therapeutic action by regulating PTEN in a model of Sjögren's disease

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Inhibition of DAI refrains dendritic cells from maturation and prolongs murine islet and skin allograft survival

“…Allograft rejection is a complex process involving an array of events, central to which is the T-cell-mediated adaptive immune response initiated by activated DCs ( 17 ). PRRs are expressed mainly on APCs and initiate signaling pathways that trigger innate immunity, which induces DCs maturation and activation ( 18 – 20 ).…”

“…Subsequently, we further explored the immunoregulatory mechanisms of DC-DAI-RNAi in vivo . It is recognized that CD4 + T cell-mediated cellular immunity plays a vital role in allograft rejection, and their immunological properties differ by different subsets: Th1 and Th17 cells typically promote inflammatory immune responses, while Treg cells can inhibit immune responses ( 17 ). The directional differentiation of CD4 + T cells largely depends on the cytokine pattern and expression level of APCs co-stimulatory molecules.…”

The immunomodulation role of Th17 and Treg in renal transplantation

“…In vivo studies have shown that bortezomib can increase the number of Tregs, can significantly reduce the proportion of Th17 cells, and can also improve renal function and graft survival ( 82 ). In rats after KT under carbamylated erythropoietin (CEPO) treatment, it was found that CEPO significantly extended the survival time of the allograft, and flow cytometry showed that Th17/Treg ratio decreased significantly ( 83 ). These results indicate that effective treatment can prolong the survival time of kidney grafts, accompanied by the improvement of Th17/Treg ratio.…”